Objective To investigate the effect of WNK2 on the ERK1 / 2 / ROS / SHP2 signaling pathway in hepatocellular carcinoma (HCC) and to explore its role in cell proliferation and migration in HCC. Methods HepG2 cells were transfected with WNK2-mimic, sh-RNA WNK2, and corresponding negative control. The effect of WNK2 on the proliferation of HCC was examined by subcutaneous tumorigenesis assay in BALB/ c nude mice. The expressions of WNK2,p40, gp90, p-SHP2, p-AKT, and p-ERK1 / 2 in tumor tissues were detected by Western Blot. After treatment with SHP2 inhibitor PHPS1, the expressions of WNK2, P40, gp90, p-SHP2, p-AKT, and p-ERK1 / 2 in HepG2 cells were detected by Western Blot. The migration ability and invasion ability of HepG2 cells were detected by cell scratch assay and Transwell. The proliferation ability of HepG2 cells was detected by monoclonal proliferation assay. Results Compared with the sh-NC group, the tumor volume of nude mice in the sh-RNA WNK2 group was significantly increased ( P<0. 01); Compared with the NC-mimic group, the tumor volume of nude mice in the WNK2-mimic group was significantly reduced (P< 0. 01). Western Blot result showed that compared with the sh-NC group, the expression of WNK2 in the shRNA WNK2 group was significantly decreased (P< 0. 01), while the expressions of p40, gp90, p-SHP2, p-AKT and pERK1 / 2 were significantly increased (P< 0. 01). Compared with the NC-mimic group, the expression of WNK2 was significantly increased in the WNK2-mimic group (P< 0. 01), and the expressions of p40, gp90, p-SHP2, p-AKT, and p-ERK1 / 2 were significantly decreased (P< 0. 01). In vitro experiment, compared with the sh-NC group, the expression of WNK2 was significantly decreased in the sh-RNA WNK2 group (P< 0. 01), while the expressions of p40, gp90, pSHP2, p-AKT and p-ERK1 / 2 were significantly increased in the sh-RNA WNK2 group (P< 0. 01). Compared with the sh-NC + PHPS1 group, the expression of WNK2 was significantly decreased in the sh-RNA WNK2 + PHPS1 group (P<0. 01), while the expressions of p40, gp90, p-SHP2, p-AKT, and p-ERK1 / 2 were reversed and had no significant differences compared with the sh-NC + PHPS1 group (P> 0. 05). The cell scratch assay and Transwell result showed that the migration and invasion ability of HepG2 cells in the sh-RNA WNK2 group was significantly increased compared with the sh-NC group (P< 0. 01). The migration and invasion ability of HepG2 cells in the sh-NC + PHPS1 group and sh-RNA WNK2 + PHPS1 group were significantly decreased with no significant difference ( P> 0. 05 ). The result of the monoclonal proliferation experiment showed that the proliferation capacity of HepG2 cells in the sh-RNA WNK2 group was significantly increased compared with the sh-NC group (P< 0. 01), while the proliferation ability of HepG2 cells in the shNC + PHPS1 group and sh-RNA WNK2 + PHPS1 group was significantly decreased with no significant difference (P>0. 05). Conclusions WNK2 can inhibit the ERK1 / 2 / ROS / SHP2 signaling pathway, thereby inhibiting ERK1 / 2 / Akt signaling and delaying the proliferation and migration of HCC.